The overarching hypothesis of our translational program is that judicious manipulation of the tumor microenvironment can improve treatment outcome. This application builds upon discoveries made by the Program investigators during the current funding period (2006-2011), that the local and distal stroma collaborate with cancer cells to thwart the effectiveness of anti-VEGF treatments (current Projects 1 and 2) and/or to reduce the delivery and effectiveness of conventional therapeutics (current Project 3). The new Projects 1, 2 and 3 leverage our observation that both common (SDF1a/CXCR4) and specific (ANG2, IL-6, MEK) pathways are activated during anti-VEGF treatments of human glioblastoma, colorectal and hepatocellular carcinomas and this activation correlates with tumor progression during anti-VEGF treatment. Remarkably, the source of these molecules and their target cells are different in each disease, underscoring the need for careful, systematic and separate, yet complementary, molecular and cellular dissection of these pathways for improving outcome in each tumor type. Project 4 leverages the finding that paracrine interactions between tumor-associated fibroblasts and cancer cells contribute to desmoplasia and reduce the blood supply in pancreatic tumors via angiotensin 11 and its downstream effectors, including SDF1a/CXCR4. To this end, all four Projects will test the causal role of the proposed pathways by genetic and pharmacologic inhibition. The pathophysiological consequences on the tumors will be examined using cutting-edge imaging technologies, also developed during the current grant period. Each Project will be supported by (i) a common Bioengineering & Biostatistics Core (Core A), which will continue to provide statistical support and state-of the- art imaging enabling molecular, cellular, anatomical and functional dissection of tumors in their natural microenvironment; (ii) a shared Molecular, Cellular and Morphological Core (Core B) to complement the imaging approaches; (iii) a common Surgery and Animal Core (Core C) known for developing innovative pre clinical models that faithfully capture the clinical situation; and (iv) an Administrative Core (Core D) to provide administrative support and facilitate exchange and dissemination of scientific information.